8. Heredity and external factors

Genes
Long strands of DNA are present in every nucleus-containing cell. They consist for approx. 1% of genes (2). In humans, each cell nucleus contains approx. 20,000 genes containing the codes for the production of more than 100,000 different proteins (2). Not every deviating gene-variant causes an illness or disorder: most disorders are the result of a combination of gene-variants. For example, juvenile diabetes and adult-onset diabetes are based on 19 and 40 different gene-variants respectively. Which, in part or all combined, enable the development of diabetes type 1 and type 2 respectively. But MODY (diabetes type 3) is caused by the presence of only one single deviating gene-variant in the DNA. All genes, including the deviating variants, are passed on from one generation to the next.

Juvenile diabetes
With respect to the hereditary predisposition for juvenile diabetes, 19 different deviating gene-variants can contribute to the actual development of the disease (2). But each of these variants does not contribute equally. One of them is the HLA-gene (Human Leucocyte Antigen), which determines the predisposition for type 1 diabetes for 70% (2). The other 18 each contribute in part to the remaining 30% of the hereditary predisposition. It is not necessary that all 19 gene-variants are present in the DNA in order to develop type 1 diabetes: several gene-variants code for different deviations in the immune system. And thus there are various ways to develop T1D and at different speeds. But sooner or later pancreatic β cells are shut down, leading to type 1 diabetes. The age at which the diabetes symptoms develop generally varies between age 2 and 20.

External factors
The development of juvenile diabetes may vary from one individual to another, even if the same gene-variants are present in the DNA like in identical twins. If one of them were to develop juvenile diabetes, then this does not mean that the other one will automatically develop diabetes as well. That chance is found to be only 36% (2). And so it takes more than the presence of a number of gene-variants in the DNA to actually develop type 1 diabetes. Other non-hereditary factors must also play a role in the manifestation of the hereditary predisposition. Which is why it is called a ‘multi-factor hereditary disease’. In the case of T1D, the gene-variants contain the code for the production of certain T-lymphocytes that are ‘hostile’ towards the β-cells in the pancreas. External factors initiate that auto-immune reaction as a result of which β-cells are eliminated. But many generations of juvenile diabetics and centuries later it is still unclear which factors play a role. What is certain about the heredity: type 1 diabetes does not develop if none of the 19 deviating gene-variants are present in the DNA.

Offspring
As the development of juvenile diabetes can depend upon a varying number of 19 deviating genes, the risk that someone will pass the disorder on to her/his children varies between 1 to 10% (2). The risk is 10% if the parent concerned developed diabetes at an early age, i.e. prior to the 11th birthday. Then many of the gene-variants are present in the DNA. If both of the parents have juvenile diabetes, then the risk for their children is 10 to 25%, depending upon the number of variants in the DNA of each of the parents (2). DNA-analysis detects deviating gene-variants (9). So general application of that technique in diagnosing diabetes will reveal a wealth of information about the origin of T1D, which will serve future parents to decide about offspring. Because no one wants a life with diabetes for her or his child.

Adult-onset diabetes
The tendency to develop adult-onset diabetes is also genetically determined: the family connection is even more evident than it is for juvenile diabetes. Not all of the deviating gene-variants that are responsible for the development of diabetes type 2 are known as yet, but 40 have been identified (5). How fast or rather how slow the symptoms of the disease will develop and at which age the disorder becomes manifest will mainly depend upon the number and the type of gene-variants that are present in the DNA. Thus the TCF7L2-gene (TransCription Factor 7 Like 2) is of great influence (6). The relative significance of the other 39 mutants is yet to be cleared up. The risk of developing the disorder later on for the children if one or both parents have adult-onset diabetes, is not yet known (2).

Ethnic differences
The risk of developing type 2 diabetes is found to be considerably higher for Hindustani, but also for Moroccan and Turkish people, compared to autochthonous Dutch inhabitants (5). Whether more or other gene-variants play a role in these ethnic differences is not known. Sufficient DNA research is still lacking. In comparing genetic predispositions of people from various population groups, differences in nutrition, physical exercise, smoking and stress must also be considered because these factors vary considerably between groups. And exactly these external factors may trigger the hereditary predisposition for T2D to become manifest. So type 2 diabetes is also a multi-factor hereditary disease. The same applies here: adult-onset diabetes does not develop if the deviating genes in the DNA are completely absent, irrespective if you belong to an ethnic risk group and irrespective of overweight, high blood pressure, lack of exercise and smoking habits. Conversely, people who do have all of the bad variants in their DNA can postpone the development of diabetes by leading a healthy life. Nevertheless, it is nearly inevitable that they eventually develop adult-onset diabetes.

MODY
MODY is the third type of diabetes that is genetically determined. It is distinguished from diabetes type 1 and 2 by its alternate pattern of inheritance: the genetic profile in MODY contains only one single deviating gene. That gene is dominant but it isn’t always about the same variant: at least 10 different gene-variants can single-handedly cause type 3 diabetes (1). In Europe MODY3 is the most common type. It depends on a mutation in the gene HNF1A (Hepatocyte Nuclear Factor 1 homeobox A) and it causes a serious course of the illness (7). On the other hand, MODY2 is a mild form of type 3 diabetes (1). It is caused by a hereditary variant in the glucokinase-gene (8). Therefore, DNA-research is required for the differential diagnosis of MODY types 1-10. And with that, the distinction between MODY and juvenile or adult-onset diabetes will become evident as well. Because each causing gene is dominant, half of the children of a parent with type 3 diabetes will develop the same disorder.

Conclusions
1. Juvenile diabetes is a hereditary disorder that is induced by external factors; but type 1 diabetes will not develop if none of the deviating gene-variants are present in the DNA.
2. The risk of developing T1D for children of a parent with juvenile diabetes varies between 1 to 10 %; the risk is 10 to 25% if both parents have type 1 diabetes.
3. Adult-onset diabetes is a hereditary disorder that is induced by external factors; but type 2 diabetes will not develop if none of the deviating gene-variants are present in the DNA.
4. The risk of developing T2D for children of parents with adult-onset diabetes is as yet unknown.
5. MODY(1-10) is an hereditary form of diabetes that is caused by only one single dominant gene-variant.
6. The chance of developing the same disorder for children of a parent with any type of MODY is 50%.